EZH2 upregulates the PI3K/AKT pathway through IGF1R and MYC in clinically aggressive CLL
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ABSTRACT:
PROVIDER: PRJNA475984 | ENA |
REPOSITORIES: ENA
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Project description:In this study, using ChIP sequencing, we identified EZH2 target genes in two prognostic subgroups of chronic lymphocytic leukemia with distinct outcome, i.e. IGHV-unmutated/subset #1 and IGHV-mutated/subset #4. Our data identified many oncogenic pathways enriched equally by EZH2 target genes in both prognostic subgroups. Importantly, we identified PI3K pathway as differentially enriched pathway by EZH2 between the two prognostic sub groups. Validation of EZH2 target genes for EZH2 occupancy on selected PI3K pathway target genes were performed using independent CLL patient samples and CLL cell lines using siRNA mediated down regulation and ChIP assays. In conclusion, for the first time we characterized EZH2 target genes in CLL to understand the role of EZH2 in regulating the oncogenic pathways for improved therapeutic intervention and designing better drugs for targeting EZH2 in CLL.
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Project description:Stabilizing mutations of NOTCH1 have been identified in about 10% of chronic lymphocytic leukemia (CLL) cases at diagnosis, with a higher frequency in unmutated IGHV (IGHV-UM) CLL, chemorefractory CLL and CLL in advanced disease phases. Clinically, the presence of NOTCH1 mutations is an independent predictor of overall survival in CLL and associates with resistance to anti-Cd20 immunotherapy. The Gene Expression Profile was generated to identify the peculiar molecular signatures of NOTCH1 mutated CLL in the context of IGHV-UM CLL. Constitutive gene expression in CLL cells bearing or not NOTCH1 mutation (c.7541_7542delCT). Five samples were selected for each category (WT vs MUT).
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Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors. Two-subset of B cells, QF vs PF. 8 samples of 4 patients.
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